alpha-Synuclein Activates Microglia by Inducing the Expressions of Matrix Metalloproteinases and the Subsequent Activation of Protease-Activated Receptor-1open access
- Authors
- Lee, Eun-Jung; Woo, Moon-Sook; Moon, Pyong-Gon; Baek, Moon-Chang; Choi, In-Young; Kim, Won-Ki; Junn, Eunsung; Kim, Hee-Sun
- Issue Date
- 1-Jul-2010
- Publisher
- AMER ASSOC IMMUNOLOGISTS
- Citation
- JOURNAL OF IMMUNOLOGY, v.185, no.1, pp 615 - 623
- Pages
- 9
- Indexed
- SCI
SCIE
SCOPUS
- Journal Title
- JOURNAL OF IMMUNOLOGY
- Volume
- 185
- Number
- 1
- Start Page
- 615
- End Page
- 623
- URI
- https://scholarworks.korea.ac.kr/kumedicine/handle/2020.sw.kumedicine/14707
- DOI
- 10.4049/jimmunol.0903480
- ISSN
- 0022-1767
1550-6606
- Abstract
- The mutation or overexpression of alpha-synuclein protein plays a pivotal role in the pathogenesis of Parkinson's disease. In our preliminary experiments, we found that alpha-synuclein induced the expression of matrix metalloproteinases (MMPs) (MMP-1, -3, -8, and -9) in rat primary cultured microglia. Thus, the current study was undertaken to determine the roles of MMPs in alpha-synuclein-induced microglial activation. The inhibition of MMP-3, -8, or - 9 significantly reduced NO and reactive oxygen species levels and suppressed the expression of TNF-alpha and IL-1 beta. Notably, MMP-8 inhibitor suppressed TNF-alpha production more efficaciously than MMP-3 or MMP-9 inhibitors. Inhibition of MMP-3 or - 9 also suppressed the activities of MAPK, NF-kappa B, and AP-1. Previously, protease-activated receptor-1 (PAR-1) has been associated with the actions of MMPs, and thus, we further investigated the role of PAR-1 in alpha-synuclein-induced inflammatory reactions. A PAR-1-specific inhibitor and a PAR-1 antagonist significantly suppressed cytokine levels, and NO and reactive oxygen species production in alpha-synuclein-treated microglia. Subsequent PAR-1 cleavage assay revealed that MMP-3, -8, and - 9, but not alpha-synuclein, cleaved the synthetic peptide containing conventional PAR-1 cleavage sites. These results suggest that MMPs secreted by alpha-synuclein-stimulated microglia activate PAR-1 and amplify microglial inflammatory signals in an autocrine or paracrine manner. Furthermore, our findings suggest that modulation of the activities of MMPs and/or PAR-1 may provide a new therapeutic strategy for Parkinson's disease. The Journal of Immunology, 2010, 185: 615-623.
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Collections - 1. Basic Science > Department of Neuroscience > 1. Journal Articles
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